Background: One of the promising scaffolds in drug discovery is the fused pyrimidine derivatives.
Objective and Method: Efficient synthesis of a novel series of 18 new 1,8-naphthyridine-3-carbonitrile, 2-amino
pyrido[2,3-d]pyrimidine derivatives via multi-component reactions of aromatic aldehydes, active methylene,
and an aromatic amine under microwave irradiation and evaluation of their anticancer activity and possible
Results: Only compounds 5 (a-c) had a significant antiproliferative activity in hepatic HepG2 cells at submicromolar
concentration (7.5-10 µM). Similarly, only compound 11 (a-c) had a significant activity in breast
MCF7 cells at (4-7 µM). Derivatives with one methoxyphenyl substitution (5a and 11a) were not different from
derivatives having dimethoxyphenyl substitution (5b and 11b). However, thiophene substitution (5c and 11c)
enhanced the anticancer activity in both cells lines examined by 25% in HepG2 and by ~45% in MCF7 cells
compared to a and b derivatives. All compounds were safe to both normal human lung cells (WI-38) and RBCs
at concentrations up to 40 mM. The antiproliferative activity of compounds 5 (a-c) in HepG2 could be attributed
to an induction of intrinsic apoptotic pathway as evidenced from the induction of initiator caspase 9 by ~ 4 folds.
While, the activity of compounds 11 (a-c) could be attributed to their potential to inhibit tyrosine kinases (TK)
by up to 85%. The IC50 of derivative 11c against TK was at 173 nM.
Conclusion: The present study reported that derivatives 5 and 11 have merit for further investigation as anticancer
and TK inhibitors.